Substituted xanthines as modulators of TRPC5 activity
Inventors
Assignees
Hydra Bioscienes LLC • Boehringer Ingelheim International GmbH • Boehringer Ingelheim Pharma GmbH and Co KG
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Publication Number
US-12291532-B2
Publication Date
2025-05-06
Expiration Date
Abstract
The present invention relates to compounds of formula (I) a process for their manufacture, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment of conditions having an association with TRPC5 containing ion channels. R1, R2, R3, R4 and R5 have meanings given in the description.
Core Innovation
The invention relates to substituted xanthine derivatives of formula I, or stereoisomers thereof, as modulators of TRPC5 (transient receptor potential cation channel subfamily C member 5). The disclosed compounds are defined by specific substituent constraints including R1, R2, R3, R4, and R5 options, with permitted fluorine and/or C1-C3 fluoroalkyl substitutions. The structural differentiation described includes a change to a 2-pyrazinyl group at the C8 position and a heteroaryl-O group modification compared with WO2014/143799.
The patent describes that the compounds inhibit TRPC5-mediated ion flux and TRPC5-mediated transient receptor potential cation channel current. Assay A (patch clamp) is provided as an experimental basis for demonstrating inhibition, and activity benchmarks are reported for invention examples. The disclosure states that the compounds show higher potency than prior art, with reported IC50 values including examples such as about 52 nM versus 324 nM in a prior-art comparison.
The invention further characterizes the disclosed compounds for therapeutic and preventative use in TRPC5-associated conditions. Pharmaceutical composition and administration contexts are provided, including general dosing and combination therapy concepts. The patent also provides assay use and treatment indication categories spanning psychiatric, neurological and neurodegenerative, pain, seizure, non-neuronal, and cancer contexts, tied to inhibiting TRPC5-mediated current.
Claims Coverage
The independent claims cover 5 inventive features across compound, salt, cell, subject, and condition-based methods. The core claimed inventive structure includes formula I substituted xanthine derivatives with defined R1-R5 substituent constraints, including fluorine and optional C1-C3 fluoroalkyl substitution at R5.
Substituted xanthine compounds of formula I as TRPC5 modulators
A compound of formula I, or a stereoisomer thereof, wherein R1, R2, R3, R4, and R5 are defined with the stated options, including permitted fluorine substituents and optional C1-C3 fluoroalkyl substitution at R5.
Pharmaceutically acceptable salts of formula I compounds
A pharmaceutically acceptable salt of a compound of formula I, or a stereoisomer thereof, wherein R1, R2, R3, R4, and R5 are defined with the stated options, including permitted fluorine substituents and optional C1-C3 fluoroalkyl substitution at R5.
Inhibiting TRPC5-mediated transient receptor potential cation channel current in cells
A method of inhibiting TRPC5-mediated transient receptor potential cation channel current in a cell by contacting the cell with an effective amount of the compound or stereoisomer.
Inhibiting TRPC5-mediated current in a subject by administration of a formula I salt
A method of inhibiting a TRPC5-mediated current in a subject by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a formula I compound or a stereoisomer thereof.
Treating TRPC5-associated neurodegenerative, neurological, or psychiatric conditions
A method in which the TRPC5-mediated inhibition is carried out for a subject having a TRPC5-mediated transient receptor potential cation channel C subfamily member 5 condition or disorder selected from the listed neurodegenerative, neurological, or psychiatric categories.
The claim coverage centers on formula I substituted xanthine derivatives, including stereoisomers, with defined R1-R5 substituent constraints, including fluorine and optional C1-C3 fluoroalkyl substitution at R5. The disclosed methods cover inhibiting TRPC5-mediated transient receptor potential cation channel current in cells and in subjects via effective contact or administration of therapeutically effective amounts, with further dependent coverage specifying TRPC5-associated neurodegenerative, neurological, and psychiatric conditions and selected disorder subtypes.
Stated Advantages
Higher potency than prior art, as supported by reported IC50 value comparisons and patch clamp (Assay A) measurements.
Documented Applications
Therapy and prevention for TRPC5-associated conditions, using compounds that inhibit TRPC5-mediated ion flux and TRPC5-mediated transient receptor potential cation channel current.
Treatment of TRPC5-mediated condition or disorder categories including neurodegenerative, neurological, and psychiatric conditions and disorders.
Selected disease/disorder examples enumerated for application include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, anxiety, pain, and disorders associated with addiction, dysregulated emotional processing, impaired impulse control, fear-related disorder, memory disorder, and brain disorders caused by aging or trauma.
Disorders associated with dysregulated emotional processing, specifically borderline personality disorder or a depressive disorder.
Depressive disorder subtype selection includes bipolar disorder, dysthymia, major depression, major depressive disorder, postpartum depression, and psychiatric depression.
Use across psychiatric, neurological/neurodegenerative, pain, seizure, non-neuronal, and cancer contexts is described in the provided content.
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